Angiogenesis refers to the physiological process involving the formation or growth of new blood vessels from pre-existing vessels. Angiogenesis may be generally controlled by certain chemicals produced in the body. Some of these chemicals stimulate cells to repair damaged blood vessels or form new ones. Other chemicals, such as angiogenesis inhibitors, signal the process to stop.
Therapeutic angiogenesis is the application of specific compounds which may inhibit or induce the creation of new blood vessels in the body in order to combat diseases. The therapeutic application of the principle “angiogenesis” can be divided into two main areas, i.e., anti-angiogenic therapies and pro-angiogenic therapies. The pro-angiogenic therapies generally involves inducing the creation of new blood vessels for treating or preventing cardiovascular diseases, atherosclerotic diseases and related diseases such as coronary heart disease, peripheral arterial disease and wound healing disorders. On the contrary, the anti-angiogenic therapies generally involves inhibiting the creation of new blood vessels for treating cancers, tumors and malignancies.
Angiogenesis can play an important role in the growth and spread of cancer, tumor and malignancy. For example, new blood vessels can feed the cancer or tumor cells with oxygen and nutrients, allow these cells to grow, invade nearby tissue, spread to other parts of the body, and form new colonies of cancer cells.
Angiogenesis inhibitors or antiangiogenic agents, such as fumagillin and derivatives thereof, are expected to be of great clinical potential in treating many diseases, such as solid tumors, diabetic retinopathy, rheumatoid arthritis, psoriasis and obesity (Folkman, J. Nat. Med. 1995, 1, 27). Recent clinical studies showed that when given in combination with chemotherapies, some antiangiogenic agents produced much better responses (Jain, R. K. Science 2005, 307, 58 and references therein) than chemotherapies alone. It is also reported that fumagillin may be used to treat intestinal infections, such as intestinal microsporidiosis or amebiasis.
Among antiangiogenic agents, fumagillin and its natural or synthetic derivatives, have received close attention because of their biological activities. For example, 5-demethoxyfumagillol is a potent angiogenesis inhibitor isolated in 2004 from Aspergillus fumigatus by D. Kim et al. The structure of 5-demethoxyfumagillol was confirmed by an independent synthesis from fumagillol (Kim, D.; Min, J.; Ahn, S. K.; Lee, H. W.; Choi, N. S.; Moon, S. K. Chem. Pharm. Bull. 2004, 52, 447). The X-ray structure of a MetAP-2-fumagillin complex (Liu, S.; Widom, J.; Kemp, C. W.; Crews, C. M.; Clardy, J. Science 1998, 282, 1324) suggests that generally fumagillin-related compounds selectively and irreversibly inhibit the cobalt-containing type II methionine aminopeptidase (MetAP-2) in the same manner as fumagillin.
The suggested mechanism has been directing the drug design of fumagillin and related natural product derivatives based on such structure-activity relation. For example, TNP-470, a fumagillin derivative, can effectively block tumor growth and metastasis in animal models, and showed promise in phase I/II clinical trials. However, further clinical trials of TNP-470 was stymied by its low half-life values, neurotoxic side effects (fatigue, vertigo, ataxia and loss of concentration) and possible disruption of normal angiogenic process (femal reproductive system, wound healing). Such undesirable properties and side effects generally limit the widespread use of TNP-470 as an anticancer agent ((a) Kruger, E. A.; Figg, W. D. Expert Opin. Invest. Drugs 2000, 9, 1383; (b) Griffith, E. C.; Su, Z.; Turk, B. E.; Chen, S.; Chang, Y.-H.; Wu, Z.; Biemann, K.; Liu, J. O. Chem. Biol. 1997, 4, 461).
Recently, fumagillin derivatives PPI-2458 (Bernier, S. G.; Lazarus, D. D.; Clark, E.; Doyle, B.; Labenski, M. T.; Thompson, C. D.; Westlin, W. F.; Hannig G. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 10768) and CKD-732 (Kim, E.-J.; Shin, W.-H. Biol. Pharm. Bull 2005, 28, 217) have entered into phase I clinical trials in cancer and other diseases. However, both PPI-2458 and CKD-732 have rather complicated structures.
Thus there is a need for further fumagillin derivatives for treating cancer and other diseases. Further, there is a need for angiogenesis inhibitors that are easier to prepare and/or have no or reduced undesirable properties and/or side effects.